The goal of this project is to explore the mechanisms of action and the efficacy of phenylacetate, its pro-drug phenylbutyrate, and analogs in treatment in malignant disorders of cell differentiation. The major observations are: l. Activity in Prostate Ca. NaPa was found to induce selective cytostasis and phenotypic reversion in androgen-independent PC3 and DU145 prostate cell lines. Loss of malignant properties (e.g., invasiveness and tumorigenicity in athymic mice) was accompanied by alterations in the expression of genes implicated in autocrine growth, immunosuppression and metastasis. NaPA enhanced the efficacy suramin, a drug with demonstrable activity in patients. 2. Activity in Brain Ca. NaPA has been used in damage to immature brain in phenylketonuria. Because of similarities in growth pattern and metabolism between developing normal brain and malignant central nervous system tumors, we speculated that phenylacetate caused selective suppression of glioblastoma growth in vitro and in rat models. Inhibition of the mevalonate pathway of cholesterol synthesis was identified as a potential mechanism underlying activity in PKU and cancer. Our data suggest that phenylacetate and phenylbutyrate, NaPA might offer a safe and effective new approach to treatment of advanced prostate and brain cancer. Phenylbutyrate may be active in sickle cell and thalassemia. Phase I clinical trials with phenylacetate and phenylbutyrate in treatment of adults with cancer are progressing.